The nitroaldol or Henry reaction is one of the classical C, C- bond forming processes. Referring to Scheme I, the nitroaldol reaction furnishes the 1, 2 -functionalized nitro alcohols A, precursors of the symmetrical (R.sup.1 =R.sup.2) and nonsymmetrical (R.sup.1 .noteq.R.sup.2) aminoalcohols B.
Nitro alcohols are frequently used as intermediates in synthesis of .beta.-amino alcohol derivatives. For example, they are useful in the synthesis of Chloramphenicol, J. Controulis et al. J. Am. Chem. Soc., 1949, 71, 2463 and of ephedrine 7a, F. Hoover et al J. Org. Chem. 1967, 12, 506 and norephedrine 7b.
The nitroaldol reaction has been extensively studied, G. Verlag in Methoden der Organischen Chemie 1971 (Houben-Weyl). Vol. XII and R. G. Coombes in Comprehensive Organic Chemistry 1979 (Eds., D. Barton & W. Olles) p. 303 Pergamon, Oxford. However, in the conventional process for preparing nitro alcohols, identified as the nitroaldol or Henry reaction, there is no control of stereoselectivity, except in cyclic systems, and this problem has hardly been addressed. The lack of selectivity is due to the reversibility of the reaction and the facile epimerization at the nitro-substituted C-atom. The nitro alcohols of this type (R.sup.1 R.sup.2 =) occur in two diastereomeric forms, the erythro - (C) and the threo - (D) isomers,. A stereoselective synthesis of either of these isomers is desirable.
Seebach has reported that doubly deprotonated nitro alkanes 1 in Scheme II react with aldehydes to yield intermediate nitronate alkoxides 2, Seebach et al Helv Chim. Acta 1982 65, 1101 and Seebach et al J. Am. Chem. Soc. 1985 107 3601 It appears that kinetic reprotonation at -100.degree. C. in polar solvents yield nitro alcohols enriched in the threo diastereoisomer 3 in a ratio of erythro-threo of 47:3-18:7. Conversely, Seebach also reports the reprotonation of the t-butyldimethylsilyloxy to give nitro alkanes 4 enriched in the erythro diastereoisomer 41:9-19:1. Seebach observed high erythro selectivity 19:1-4:1 with a fluoride catalyzed reaction of silyl nitronates 5 with aldehydes under appropriate reaction conditions, such as very low temperature (below -80.degree. C.) and the use of stabilizing agents and protecting groups.
Hanessian et al., Tetrahedron Lett 1985, 16, 1261 has observed variation in selectivity in the reaction of (S)-benzyloxypropionaldehyde with methyl 3 - nitropropionate using zinc or magnesium salts and potassium t-butoxide in THF.
There is a need for a process to control the diastereoselectivity of the nitroaldol reaction without the disadvantages seen in the prior art: starting the reaction with two equivalents of base, using a highly reactive anion, using a sensitive protective group or requiring exact experimental control over the process.